Between 1993 and 1997, The Agricultural Health Study (AHS) enrolled more than 57,000 licensed applicators, 82% of eligible private pesticide applicators (largely farmers) in IA and NC and 43% of commercial applicators from Iowa. About 40% of the private applicators completed a more detailed take-home questionnaire covering farming practices and health. Nearly 32,000 spouses of farmer applicators enrolled and provided data on pesticides and health (including reproductive health), and children under age 21 at time of enrollment. Participants have completed up to three follow-up surveys in 1999-2003, 2005-2010, and 2013-2015, updating data on farming and lifestyle exposures and the occurrence of non-cancer health outcomes. Active follow-up is ongoing with a new cohort-wide survey started in 2019. The cohort is routinely linked to cancer registries in IA and NC and vital statistics to identify cancer cases and deaths and has also been linked to the U.S. Renal Data System to identify end stage renal disease. We also collected buccal-cell samples for genetic research from 40% of participants, as well as from those with some specific incident cancers and other conditions and conducted a dietary survey in 1999-2003. We conducted in-depth pesticide exposure assessments for selected chemicals in sub-samples of the cohort, and results have been used to validate study questionnaires and inform exposure classification. NIEHS researchers continue to lead AHS research on farming exposures in relation to diverse non-cancer outcomes, including neurological diseases and symptoms, respiratory outcomes, cardiovascular disease, diabetes, kidney and thyroid disease, autoimmune diseases, and age-related macular degeneration., New research on neurologic outcomes includes analyses on pre-motor symptoms and analysis of validated and confirmed incident cases of Parkinsons disease. Findings linking high pesticide exposure events to decreased sense of smell provided support for a new collaboration with investigators at Michigan State University who will be collecting additional data on loss of sense of smell as a potential pre-clinical marker associated with Parkinsons disease risk. In 2015, the AHS started a study on pesticides in relation to dementia and Alzheimer's disease, a collaboration led by investigators at Duke University. We have screened cognitive function in nearly 2500 elderly participants and identified 16% with possible Alzheimers disease or other dementias. Home visits, blood collection, and case validation efforts have been completed, and findings on enrollment pesticides and dementia were recently submitted for presentation at a national meeting. Analyses are ongoing. NIEHS research on respiratory outcomes includes earlier published findings on pesticides, wheeze and asthma, and an in-depth study of respiratory diseases involving a sub-cohort of applicators and spouses (The Lung Health Study; see report by S London). We previously reported inverse associations of perinatal and early childhood farm exposures with atopy, and an association of childhood raw milk consumption with higher lung function in adults. We also reported that pesticides may be associated with sleep apnea, and that house dust endotoxin is associated with asthma phenotype and higher counts of peripheral white blood cells., and that . Newly published research show that the diversity and specific features of the house dust microbiome are related to to farm exposures and asthma. Ongoing research is focused on genetic risk scores for pulmonary function, and DNA methylation in relation to pesticide use. Our previous research on pesticides and incident rheumatoid arthritis (RA) identified several associations with pesticides and other farming exposures in female spouses and male farmers. Or newly published findings confirmed associations of RA with chemical fertilizers, solvents and painting in a larger sample including both famers and spouses. We have also identified specific associations of lifetime pesticide use with the presence of anti-nuclear autoantibodies (ANA) in 700 male farmers. Ongoing work is examining more recent exposures in relation to ANA and investigating associations with systemic lupus erythematosus, as well as investigating pesticide use in relation to the incidence of shingles (herpes zoster), a marker of potential immune-disfunction. In the Growth and Puberty Study, we explored the feasibility of measuring early puberty markers (hormones in urine and saliva, height velocity, Tanner staging) in 60 children. Hormone assays are completed and a paper showing that certain hormones are elevated at least several months before self-reported and physiologic measures (e.g. Tanner sating and onset of menses) is under review. Analysis of hormone levels in relation to children's potential pesticide exposure is ongoing. Previous findings had identified multiple pesticide associations with thyroid disease in AHS spouses and applicators, several of which were recently confirmed along with other new associations for incident hypothyroidism in female spouses and male farmers with additional years of follow-up and increased numbers of incident cases. Findings on pesticide associations with incident hyperthyroidism were largely null. Prior findings also suggested certain pesticides were associated with diabetes. Given the increased rates of diabetes in the cohort and the general increase in diabetes with age, new analyses are underway updating these analyses and considering additional exposure data. The AHS has participated in large data pooling projects through the NCI-sponsored Cohort Consortium, specifically contributing to several large-scale pooling projects evaluating genetic and lifestyle/environmental risks for several cancers (e.g. breast, thyroid, ovarian cancers). The AHS is one of the founding members of the Agricultural Cohort Consortium (AGRICOH), and we are collaborators in new and ongoing research on asthma and neurologic outcomes. In the future, this collaboration will enhance our ability to assess rare exposures and outcomes, such as autoimmune diseases. Although cohort members have lower rates of death from some chronic diseases compared with the general population, we have previously observed elevated mortality from some specific causes, including injury and some cancers. In a new published analysis with more deaths, we have confirmed these findings and identified elevated standardized and causal mortality ratios for additional causes. Through linkage to the U.S. Renal Data System, we have previously published findings on pesticides and end-stage renal disease in farmers and spouses. Given aging-related increases in renal disease, we expect the rates of kidney disease to increase in the cohort; given the epidemic of unexplained renal failure in global agriculture, we are planning new linkages to study renal failure in the AHS. Since half of the cohort is over age 65, we recently linked the AHS to administrative healthcare data on in Medicare-eligible AHS participants. This will enable analyses of diseases that are difficult to study without validation and in participants lost to follow-up, reducing participant burden while facilitating research on aging-related diseases. Over the years, the Agricultural Health Study has contributed to our knowledge on potential health effects of exposures associated with pesticides use and other farming activities. This continuously serves our ultimate goal of improving the health of US farmers and their family members.